The present invention relates to low-substituted hydroxypropylcellulose that is added for providing disintegration or compressibility at the time of production of a preparation, in the field of medicines, foods, or the like. More specifically, the present invention relates to low-substituted hydroxypropylcellulose that is excellent in particular in compressibility and disintegration.
In solid dosage forms in the field of medicines, foods, or the like, a preparation produced only from a principal ingredient has the problems that the drug action may not be sufficiently exerted because sufficient disintegration is not obtained when the drug is administered, and that the shape of a tablet or a granule produced therefrom may not be kept due to its poor compressibility. In this case, the disintegration can be improved by adding a disintegrant such as low-substituted hydroxypropylcellulose, calcium salts of carboxymethyl cellulose, crosslinked carboxymethylcellulose sodium, crosslinked polyvinylpyrrolidone, or carboxymethyl starch. Furthermore, the compressibility can be improved by adding crystalline cellulose or a water-soluble binder. Low-substituted hydroxypropylcellulose is known as a unique additive having both of the disintegration and the compressibility.
Since low-substituted hydroxypropylcellulose is nonionic, there is an advantage in that alteration is less caused by reaction with an ionic drug, for example. Japanese Patent Application Examined Publication Nos. 48-38858/1973 and 57-53100/1982 described that low-substituted hydroxypropylcellulose can be used as an additive of medicines.
As described in Japanese Patent Application Examined Publication No. 48-38858/1973, Japanese Patent Application Examined Publication No. 57-53100/1982, Japanese Patent Application Unexamined Publication No. 10-305084/1998, Japanese Patent Application Unexamined Publication No. 11-322802/1999, and Japanese Patent Application Unexamined Publication No. 7-324101/1995, examples of a method for preparing alkali cellulose include a method in which sheet-shaped pulp is immersed in an aqueous sodium hydroxide solution and then squeezed. In this method, sheet-shaped pulp is immersed in an aqueous sodium hydroxide solution, and thus an excessive amount of aqueous sodium hydroxide solution is absorbed by the pulp. Accordingly, when the pulp is squeezed, all that is produced is alkali cellulose containing an excessive amount of water or sodium hydroxide. Thus, the selectivity for side reactions increases, and the efficiency of etherification, which is a main reaction, is low.
As described in Japanese Patent Application Unexamined Publication No. 10-305084/1998, conventional low-substituted hydroxypropylcellulose can be obtained by reacting alkali cellulose and propylene oxide. In etherification, cellulose is etherified as a main reaction, and propylene glycol is produced as a side reaction due to reaction between propylene oxide and water. The amount of propylene oxide used for this etherification varies depending on the amount of aqueous sodium hydroxide solution used as a reaction catalyst, and there is the problem that the reaction efficiency is lowered when the amount of water or sodium hydroxide in the alkali cellulose is too large.
On the other hand, a production method in which an aqueous sodium hydroxide solution is dropped or sprayed and thus mixed with powdered pulp is advantageous in that the amount of water of sodium hydroxide in the alkali cellulose can be freely adjusted.
Furthermore, as described in Japanese Patent Application Unexamined Publication No. 10-305084/1998, in a case where a crude reaction product is dissolved by loading the reaction product into hot water containing acids during neutralization of alkali remaining in the crude reaction product, then obtained low-substituted hydroxypropylcellulose is in the form of fibers as in the raw material pulp, is excellent in washability, and can be easily refined, but it is poor in milling characteristics, and thus a powder having excellent flowability cannot be obtained.
Japanese Patent Application Examined Publication No. 57-53100/1982 described a method for controlling fiber portions by partially neutralizing alkali used as a reaction catalyst in water, and partially dissolving low-substituted hydroxypropylcellulose, after completion of etherification. It was described that in this method, when the amount of alkali remaining is increased, the amount of fibrous substances is reduced due to dissolution, so that an obtained milled product has high bulk density and good flowability, but the washability is lowered at the time of refinement.
Japanese Patent Application Unexamined Publication No. 10-305084/1998 described that when the water content of a washed and dehydrated product is 70 to 90% by weight, the milling characteristics are improved, and thus a low-substituted hydroxypropylcellulose powder can be obtained that has a degree of compression of 42% or less and a repose angle of 48° or less. It was also described that milling is performed using an impact-type mill such as a hammer mill.
However, in an impact-type mill, a product is easily affected by the influence of a milling raw material, and the powder properties of the product are determined by the shape of the milling raw material. More specifically, when milling, with an impact-type mill, fibrous raw materials that are obtained by increasing the partial neutralization amount as in Japanese Patent Application Unexamined Publication No. 57-53100/1982, or by performing neutralization by loading a reaction product into water or hot water containing acids in an amount equivalent to sodium hydroxide that remains in the crude reaction product, without performing a dissolution step, then the obtained milled product is a powder containing a large amount of fibrous particles and having low flowability. Furthermore, this method has low throughput and low productivity because milling is performed by applying high energy in a short time.
Furthermore, low-substituted hydroxypropylcellulose produced by the above-described method has a problem in that when dissolution is performed with a smaller partial neutralization amount in order to improve the flowability of a powder, the amount of fiber portions is reduced and thus the compressibility is lowered. Furthermore, when the amount of fiber portions is increased by increasing the partial neutralization amount in order to improve the compressibility, there is a problem in that the flowability is lowered.
The powder obtained according to Japanese Patent Application Unexamined Publication No. 10-305084/1998, in which the water content of a washed and dehydrated product is controlled to 70 to 90% by weight, contains fibrous particles and spherical particles in a mixed manner. Due to the influence of the fibrous particles, the flowability is insufficient. Thus, when a tablet is produced by direct tableting, the weight variation of the tablet may be large. Furthermore, due to low compressibility of the spherical particles, the compressibility of the mixed powder is insufficient.
Japanese Patent Application Unexamined Publication No. 11-322802/1999 described that when fibrous particles are completely dissolved, low-substituted hydroxypropylcellulose having high flowability can be obtained. However, the compressibility of a powder obtained by this method is low.
Furthermore, Japanese Patent Application Examined Publication No. 57-53100/1982 described that when milling is performed using a ball mill instead of impact milling, the compressibility is poor. Moreover, when milling is performed using a ball mill, the swelling properties, which are important properties as a disintegrant, are low.
Japanese Patent Application Unexamined Publication No. 2001-9316 described water-soluble cellulose ether in which a vertical roller mill is used for powdering pulp, and thus the bulk density of the powdered pulp is increased, so that the amount of fibers that are not dissolved when the cellulose ether is dissolved in water is small.
However, water-soluble cellulose ether is different from water-insoluble low-substituted hydroxypropylcellulose, in that a neutralization step, which is essential for producing low-substituted hydroxypropylcellulose, is not performed. Furthermore, in Japanese Patent Application Unexamined Publication No. 2001-9316, there is no description on compressibility and disintegration, which are important properties of low-substituted hydroxypropylcellulose.
Japanese Patent Application Unexamined Publication No. 9-76233/1997 described a method for producing cellulose ether using a vertical roller mill, but this method relates not to water-insoluble low-substituted hydroxypropylcellulose but to water-soluble cellulose ether, in a similar manner.
Japanese Patent Application Unexamined Publication No. 7-324101/1995 described low-substituted hydroxypropylcellulose having a repose angle of 45° or less and a swollen volume increase ratio of 100% or more, but the compressibility of this low-substituted hydroxypropylcellulose is low.